1. Field of the Invention
The present invention relates to an oral sustained-release preparation. More particularly, the present invention is concerned with an oral sustained-release preparation which contains at least one active ingredient selected from the group consisting of fasudil hydrochloride and a hydrate thereof, the preparation comprising at least one sustained-release coated particle comprising a core having a surface and a coating formed on the surface of the core, wherein the core contains the active ingredient and the coating comprises a coating base material and a specific insoluble auxiliary material, the preparation exhibiting a specific dissolution rate with respect to the active ingredient, as measured by the dissolution test. The present invention is also concerned with a method for evaluating an oral sustained-release preparation containing the active ingredient, the evaluation being conducted with respect to the sustained-release ability of the active ingredient.
By using the oral sustained-release preparation of the present invention, it becomes possible to surely control the release of fasudil hydrochloride from the preparation, so that a desired amount of fasudil hydrochloride is continued to be released from the preparation for a long period of time, and that the effect of fasudil hydrochloride is maintained for a relatively long period of time. Therefore, the frequency of the administration of the preparation becomes low, so that the burden of the patient who has to take the preparation can be decreased and the compliance with respect to the administration of the preparation can be improved. As a result, the therapeutic effect of fasudil hydrochloride is rendered reliable. Therefore, the oral sustained-release preparation of the present invention is extremely useful.
2. Prior Art
1-(5-Isoquinolinesulfonyl)homopiperazine hydrochloride (hereinbelow referred to as xe2x80x9cfasudil hydrochloridexe2x80x9d) has excellent vasodilative activity and is clinically used for treating cerebral vasospasm (which is likely to occur after the operation of a patient suffering from subarachnoid hemorrhage), cerebral ischemic symptoms accompanying the cerebral vasospasm, and the like, wherein the above-mentioned fasudil hydrochloride is used in the form of a parenteral preparation which is available under tradename xe2x80x9cEril Inj.xe2x80x9d (registered trademark for the product produced and sold by Asahi Kasei Kogyo Kabushiki Kaisha, Japan) (see Unexamined Japanese Patent Application Laid-Open Specification No. 5-3851 (corresponding to U.S. Pat. No. 4,678,783)).
There are two conventionally known different types of crystals of fasudil hydrochloride, i.e., crystals containing no water of crystallization (hereinbelow referred to as xe2x80x9cfasudil hydrochloride anhydridexe2x80x9d) and crystals containing water of crystallization (hereinbelow referred to as xe2x80x9cfasudil hydrochloride hydratexe2x80x9d) (see International Patent Application Publication No. WO97/02260 (corresponding to EP 0 870 767 A1)).
Fasudil hydrochloride has excellent vasodilative activity. For this reason, it is expected that fasudil hydrochloride is provided in the form of various types of preparations, wherein the administration route, manner of administration, dosage and the like of the preparations are different from those of the above-mentioned parenteral preparation.
For example, due to the excellent vasodilative activity, fasudil hydrochloride can be used as a drug for treating an ischemic disease (especially, angina pectoris). With respect to a preparation containing fasudil hydrochloride as an active ingredient, which is used as a drug for treating an ischemic disease, an oral preparation can be taken by the patient himself at his home, whereas a parenteral preparation must be administered by a doctor at a hospital. Therefore, the oral preparation can extremely decrease the burden of the patient suffering from an ischemic disease, which needs his attendance at a hospital for the treatment of the disease.
From the above-mentioned viewpoint, the present inventors attempted developing an oral preparation containing fasudil hydrochloride as an active ingredient, which is used as a drug for treating an ischemic disease (such as angina pectoris).
In the course of the development of the oral preparation, it has been found that the conventional oral preparation (containing fasudil hydrochloride as an active ingredient) is required to be administered as frequently as 3 times a day for achieving a satisfactory therapeutic effect. However, with respect to a disease (such as an ischemic disease) which should be treated by administering a drug for a long period of time, when a preparation used as a drug for treating the disease should be frequently administered, in many cases, the so-called xe2x80x9ccompliancexe2x80x9d with respect to the administration of the preparation is low. This low compliance is caused by the fact that when the preparation should be frequently administered, in many cases, the patient forgets to take the preparation. As a result, the therapeutic effect of the preparation cannot be surely achieved.
For this reason, in order to surely achieve the therapeutic effect of the preparation, it is considered preferable that the frequency of the administration of the preparation is lowered so that the compliance is improved and the burden of the patient who has to take the preparation is decreased.
As an example of the method effective for lowering the frequency of the administration of the preparation, there can be mentioned a method in which the preparation is prepared in a sustained-release form. Therefore, the present inventors attempted developing a sustained-release preparation containing fasudil hydrochloride as an active ingredient. As a result, it has been found that in order to develop such a preparation, the below-mentioned two problems should be solved.
One of the two problems is how to realize a controlled dissolution of fasudil hydrochloride.
Generally, when the dissolution rate of the drug from the preparation is appropriately controlled, the drug is gradually released from the preparation (which contains a relatively large amount of the drug) over a relatively long period of time (hereinafter referred to simply as xe2x80x9cover a long period of timexe2x80x9d). When such a preparation (sustained-release preparation) is administered to a patient, a desired amount of the drug is gradually released from the preparation over a long period of time. As a result, the concentration of the drug in the blood of the patient is kept in a desired range, so that the effect of the drug is maintained for a long period of time. Further, by virtue of the effect maintained for a long period of time, the frequency of the administration of the preparation can be lowered.
There are many reports on the techniques for producing a sustained-release preparation. These techniques have been applied to many drugs, and various kinds of useful sustained-release preparations have been developed.
However, it is extremely difficult to control, by conventional methods, the release of fasudil hydrochloride from the preparation containing fasudil hydrochloride. In fact, the present inventors tried to develop a sustained-release preparation containing fasudil hydrochloride as an active ingredient using various techniques reported up to the present, but fasudil hydrochloride was rapidly released from the preparation, and it was not possible to control the release of fasudil hydrochloride. This problem is essentially caused by the fact that fasudil hydrochloride is extremely soluble in water.
In addition, in order to maintain the effect of fasudil hydrochloride for a long period of time, the concentration of the active metabolite of fasudil hydrochloride (mentioned below) in blood should be kept in a desired range for a long period of time. In order to achieve this, it is required to use a preparation in which even in the upper portion of the digestive tract (in which the amount of the internal liquid of the digestive tract is large), fasudil hydrochloride is not rapidly released from the preparation, and in which even in the lower portion of the digestive tract (in which the amount of the internal liquid in the digestive tract is small), the amount of fasudil hydrochloride released from the preparation is satisfactory.
For this reason, a sustained-release preparation containing fasudil hydrochloride as an active ingredient should exhibit the following two contradictory functions:
i) surely preventing rapid release of fasudil hydrochloride, even in the presence of a large amount of water, and
ii) surely releasing fasudil hydrochloride in a satisfactory amount for a long period of time, even in the presence of a small amount of water.
By a conventional method, it was extremely difficult to develop such a preparation.
The remainder of the two problems is how to control the kinetics of fasudil hydrochloride in a living body.
Most of fasudil hydrochloride (which is orally administered to a human) is metabolized and transferred to circulating blood. Only a small amount of fasudil hydrochloride is transferred to circulating blood without being metabolized. The main metabolite generated from fasudil hydrochloride is 1-hydroxy derivative (in which a hydroxyl group is introduced into the 1-position of the isoquinoline skeleton of fasudil hydrochloride), and this 1-hydroxy derivative exhibits pharmaceutical activities in a living body. In other words, actually, the pharmaceutical activities of fasudil hydrochloride are exhibited by this 1-hydroxy derivative (hereinafter, this 1-hydroxy derivative, which is an active metabolite derived from fasudil hydrochloride, is referred to simply as the xe2x80x9cactive metabolitexe2x80x9d). Therefore, in order to maintain the pharmaceutical activities of fasudil hydrochloride for a long period of time, the concentration of this active metabolite (not fasudil hydrochloride as such) in the blood should be kept in a desired range for a long period of time.
However, the active metabolite is rapidly eliminated from blood. Therefore, in order to keep the concentration of the active metabolite in the blood in a desired range for a long period of time, the active metabolite should be continued to be transferred to circulating blood. In order to achieve this, it is considered to be required that, during the transfer of the preparation containing fasudil hydrochloride as an active ingredient (which is orally administered) to the lower portion of the digestive tract through the entrance into the digestive tract, a desired amount of fasudil hydrochloride is continued to be released from the preparation, absorbed over the whole region of the digestive tract and metabolized to the active metabolite, and, in turn, the active metabolite is continued to be transferred to circulating blood.
However, it is conventionally known that with respect to many drugs, the absorption rate, metabolism rate and the like vary depending on the portion in the digestive tract in which the absorption, metabolism and the like of the drug occur. In some cases, the mode in which the drug is metabolized varies depending on the portion in the digestive tract in which the metabolism of the drug occurs. For this reason, the design for a sustained-release preparation (especially an oral sustained-release preparation) containing a drug which exhibits pharmaceutical activities after being metabolized (such as fasudil hydrochloride) is extremely difficult. In other words, for keeping the concentration of the active metabolite in blood in a desired range for a long period of time, it is extremely difficult to select the releasing pattern of fasudil hydrochloride from the preparation.
In this situation, the present inventors have made extensive and intensive studies with a view toward solving the above-mentioned two problems and developing an oral sustained-release preparation containing fasudil hydrochloride as an active ingredient, which releases a desired amount of fasudil hydrochloride for a long period of time and is capable of maintaining the effects of fasudil hydrochloride for a long period of time. As a result, it has been unexpectedly found that when the oral sustained-release preparation (containing fasudil hydrochloride as an active ingredient) is a preparation comprising at least one sustained-release coated particle comprising a core having a surface and a coating formed on the surface of the core, wherein the core contains the active ingredient and the coating comprises a coating base material and a specific insoluble auxiliary material, it becomes possible to surely control the release of fasudil hydrochloride from the preparation, and that the amount of water present around the above-mentioned preparation has almost no influence on the release of fasudil hydrochloride from the preparation.
Further, it has also been unexpectedly found that when the preparation containing fasudil hydrochloride as an active ingredient exhibits a specific dissolution rate with respect to the active ingredient, as measured by the dissolution test, it becomes possible to keep the concentration of the active metabolite in blood in a desired range for a long period of time.
The present invention has been completed, based on these novel findings.
Accordingly, it is a primary object of the present invention to provide an oral sustained-release preparation containing fasudil hydrochloride as an active ingredient, which releases a desired amount of fasudil hydrochloride for a long period of time and is capable of maintaining the effects of fasudil hydrochloride (exactly, the effects of 1-hydroxy derivative of fasudil hydrochloride) for a long period of time.
It is another object of the present invention to provide a method for evaluating an oral sustainedrelease preparation which contains fasudil hydrochloride as an active ingredient, the evaluation being conducted with respect to the sustained-release ability of the preparation with respect to the fasudil hydrochloride contained therein.